Suppression of major attributes of tumor-initiating cells through epithelial-mesenchymal transition

Malignant progression in cancer has been associated with the emergence of populations of tumor-initiating cells (TIC) endowed with capabilities for unlimited self-renewal, survival under stress and establishment of distant metastases. Additionally, the acquisition of invasive properties driven by the genetic program known as epithelialmesenchymal transition (EMT) may be an essential step in the evolution of neoplastic cells into fully metastatic populations. A widely accepted paradigm is that EMT potentiates tumor cell self-renewal and metastatic behaviour. Here we describe a cellular model in which a clonal population enriched in TIC expresses a genetic program distinct from a second population with traits of stable EMT, and in which both populations cooperate for enhanced local invasiveness and metastasis. Induction of the TIC-enriched population to undergo EMT by several stimuli or by constitutive overexpression of the transcription factor SNAI1 engaged a mesenchymal program while suppressing the CSC program. This suggests that TIC and EMT, contrary to current paradigms, correspond to alternative states. Furthermore, diffusible factors secreted by the population with EMT traits also induced mesenchymal reprogramming of the population enriched in CSCs. Local invasiveness in vitro and lung colonization in vivo of the TIC-enriched population was enhanced by co-injection with the EMT-trait population, and expanded the range of organs to which it metastasized. Thus, in our model, relatively stable TIC and EMT phenotypes reflect alternative genetic programs expressed by distinct clonal populations. We also suggest that dynamic cooperation between tumor subpopulations displaying either TIC or EMT traits may be a general mechanism driving local invasiveness and metastasis.

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Celià-Terrassa T, Meca-Cortés O, Mateo F, Martínez de Paz A, Rubio N, Arnal-Estapé A, Ell BJ, Bermudo R, Díaz A, Guerra-Rebollo M, Lozano JJ, Estarás C, Ulloa C, Álvarez-Simón D, Milà J, Vilella R, Paciucci R, Martínez-Balbás M, de Herreros AG, Gomis RR, Kang Y, Blanco J, Fernández PL, Thomson TM